Nuclear magnetic resonance (NMR) techniques are finding increasing use in medical diagnostics. NMR imaging, or magnetic resonance imaging (MRI) as it is sometimes known, has been found to be useful in the detection of a variety of diseases and disorders. MRI has several advantages over other imaging techniques. For example, unlike computerized tomographic methods, MRI does not employ ionizing radiation, and therefore is believed to be safer. Also, MRI can provide more information about soft tissue than can some other imaging methods.
The majority of the NMR techniques developed so far have been based on imaging of hydrogen nuclei. However, other nuclei offer potential advantages with respect to NMR. .sup.19 F in particular is of interest. The fluorine nucleus offers a strong NMR signal magnitude (high gyromagnetic ratio) similar to that of protons. Virtually no imagable fluorine exists naturally in the human body, so no background signal exists; any detectable signal comes only from whatever .sup.19 F has been administered to the subject.
.sup.19 F is a stable isotope and is naturally abundant, so there is no need for isotopic enrichment. Because its gyromagnetic ratio is about 94% that of hydrogen, existing equipment designed to image protons can be inexpensively adapted for .sup.19 F.
As a separate matter, the concept of targeting tissues using antibodies that have been radiolabeled was described years ago (Pressman, D. J. Immunol. 1949, vol. 63, pp 375-388). The advent of hybridoma technology (Kohler, G. and Milstein, C., Nature 1975, vol. 144, pp 873-881) enabled the production of monoclonal antibodies that are homogeneous, each reacting with a single epitope on an antigenic moiety.
Since then a number of monoclonal antibodies have been developed and characterized for their ability to recognize surface antigenic markers that are expressed in high levels on tumor cells and at significantly lower levels (100 to 1,000 fold less) on their normal counterparts. Several such antibodies and their fragments have been used as radiolabeled agents in cancer patients and X-ray images have been obtained (for a summary, see Biotechnology 1992, vol. 10, pp 246). Many other monoclonal antibodies and their fragments have been used in preclinical studies to obtain X-ray images of human tumor grafts in mice and cancerous or other lesions in patients.
Certain of these monoclonal antibodies target well-characterized cancer antigens such as the carcinoembryonic antigen (CEA), the TAG-72 antigen, high molecular weight milk fat globule mucin antigen (HMFG) and the like. Yet others are characterized with respect to their reactivity patterns for different tumor tissues although the molecular characterization of the reactive antigens is not complete (for example, the NR-Lu 10 antibody described by Paul Abrams and colleagues of NeoRx Corporation, B38.1 antibody described by David Colcher and his collaborators and various other antibodies described in the literature).
The use of tools of molecular biology has provided genetically engineered antibodies and their fragments which are either chimeric or humanized wherein the complementary determining regions of, e.g., a mouse monoclonal antibody is grafted into a human antibody molecule (described by Winter and his colleagues from the MRC, England). Yet additional technologies describe the use of combinatorial libraries that express antigen binding fragments encoded by human genetic sequences (described by Richard Lorner and his colleagues).
Although .sup.19 F NMR has potential benefits, there is a need for new and improved .sup.19 F-containing agents, such as .sup.19 F-labeled antibodies, which can be used in NMR imaging and spectroscopy techniques.